1. Field of the Invention
The present invention relates to substituted hydroxyureas as described further below. These compounds inhibit the enzyme 5-lipoxygenase. In addition, certain of the compounds also inhibit the enzyme cyclooxygenase. The compounds are useful for treating asthma, allergies, arthritis, psoriasis, ischemia, dermatitis, inflammation, bronchoconstriction and/or inflammatory diseases of the eye.
2. Description of the Prior Art
European Patent Application 196,184 describes an exceedingly vast array of compounds which may include hydroxyureas. The generic disclosure consists of the following structures: ##STR1## where R may be a variety of aryl-arkyl or aryl-alkenyl groups, n may be 0, m may be 1, R.sub.1 may be H and R.sub.2 may be amino, arylamino or lower alkylamino. For the cyclic cases, Z is defined as a C.sub.2 -C.sub.5 alkylene chain in which one of the carbon atoms may be replaced by a hetero atom. The compounds are lipoxygenase and/or cyclooxygenase inhibitors and are said to be useful in treating a large variety of disorders. See column 13, line 21-column 14, line 36 and column 15, line 1-column 18, line 4.
Hydroxyureas substituted by C.sub.1 -C.sub.8 alkyl groups are well known in the literature as inhibitors of ribonucleotide reductase (Parker et al., J. Pharm.Sci. 66. 1040 (1977), Larsen et al., Eur. J. Biochem. 125, 75 (1982), and consequently as anti-mitotic agents (Yu et al., J. Invest. Dermatol. 63, 279 (1974) and as inhibitors of seed germination (Clifton et al., Life Sci. 7, 993 (1968). Due to their anti-oxidant properties, they are also known as stabilizers for photographic developer compositions, e.g., FR 2,184,047, DE 2,638,525 and DE 1,926,658. U.K. 921,536 describes a process for preparing hydroxyureas of the formula RNHCON(R')OH. Hydroxyureas substituted by one or more aryl groups are also well known, due to the ready availability of aryl isocyanates.
Hydroxyureas substituted with C.sub.8 and above alkyl groups or aryl-alkyl groups are less known. The cases where R.sub.1 and/or R.sub.2 are higher alkyl have been disclosed in several patents as a photographic stabilizer, e.g., DE 2,140,462, DE 2,415,603 and U.S. Pat. No. 4,330,606. The cases where R.sub.1 and/or R.sub.2 are aryl-alkyl were generically disclosed as photo-stabilizers in the patents noted immediately above.
U.S. Pat. Nos. 4,339,515 and 4,330,606 generically disclose aralkyl hydroxyureas of the formula ##STR2## where R.sub.1 can be aralkyl. The preferred aralkyl groups contain no more than two carbon atoms in the aliphatic chain (i.e., benzyl and phenylethyl). The U.S. Pat. No. 4,330,606 patent discloses that the aralkyl groups may be substituted with the usual substituents. Methoxy is among the substituents mentioned. Both patents disclose the use of hydroxyureas in photographic emulsions or the process 23 stabilizing such emulsions with hydroxyureas. These two patents refer to U.S. Pat. No. 3,893,863 and U.S. Pat. No. 3,887,376 as prior art regarding hydroxyureas. Both U.S. Pat. No. 3,893,863 and U.S. Pat. No. 3,887,376 disclose compounds of the above formula where R.sub.1 is phenyl, p-methylphenyl, p-methoxyphenyl or p-chlorophenyl.
DE 2,845,967 (to VEB Fahlberg-List) discloses in broad terms ureas which may be substituted with, among other groups, hydroxy and aralkyl, as plant virucides.
U.S. Pat. No. 4,618,692 discloses alkyl and aralkyl hydroxyureas, which are used as intermediates in the preparation of 4-carbamoyloxy-1,3,2-oxazaphosphorins. Substantially identical disclosures are in Belgian Patents BE 899,457 and BE 900,370. Specifically disclosed is the structure ##STR3## where R.sub.1 may be benzyl, 1-phenylethyl or 2-phenylethyl, and R.sub.2 and R.sub.3 may be hydrogen.
Some related technology is described in several patents disclosing hydroxamic acids, which are lipoxygenase inhibitors useful as anti-allergy and anti-inflammatory agents. These are U.S. Pat. Nos. 4,604,407, 4,607,053, 4,605,669, 4,623,661, 3,853,905, 3,890,377, 3,972,934 and 4,001,322, and European patent application 196,674.